Cells of the substantia nigra are compromised in Parkinson's disease and related disorders, either through an hypothesized genetically programmed apoptotic pathway, or via excessive excitation coupled to the neurophysiological functions of excitatory amino acids (EAAs). These two systems may function cooperatively, although the mechanisms are poorly understood. The proposed goal of this research to investigate this possibility by evaluating the major EAA input pathways to the zona compacta of the substantia nigra (SNc), and their synaptic relationships with dopaminergic nigrostriatal systems. Since different EAA receptor subtypes exist, it is our plan to trace the interconnections between the EAA terminal arborizations, SNc EAA receptor distribution, and nigral postsynaptic transduction/gene-expression mechanisms. Anatomic and functional characterization will be conducted via immunocytochemical and electrophysiological techniques. The second part of this project relates to the molecular genetic aspects of programmed cell death in the SNc. In acutely dissociated Snc cells, apoptosis-related gene expression will be studied by subtractive hybridization followed by detailed analysis of the sequence of events related to expression, regulation and information transduction which may be linked to ionic pathways. These studies should yield information on possible apoptotic events relevant to future investigations into the subcellular mechanisms of excitotoxicity. Molecular studies will contribute to the identification of cellular markers related to the cell death process. Electro-physiological monitoring of SNc cells in vitro could give data on possible aberrations in ionic pathways, and allow further experimental design and exploration in the quest for answers.